Highlights from Recent Cancer Literature
Journal: Cancer Research (2016)

Unlike other class IA phosphatidylinositol 3′ kinase (PI3K) enzymes, PI3Kβ is activated by receptor tyrosine kinases as well as G-protein-coupled receptors (GPCR). To determine the relevance of PI3Kβ in breast cancer tumor growth and metastasis, the authors expressed a mutant construct (p110526KK-DD) that specifically abolished PI3Kβ (PIK3CB) binding to Gβγ in breast cancer cells, and assessed in vitro and in vivo abilities of the metastatic cascade. In vitro and in vivo attributes including invasion, extravasation, and gelatin degradation were inhibited upon expression of the mutant construct in p110β-silenced breast cancer cells. Accordingly, the authors have identified a novel link between GPCR and PI3Kβ in metastasis, and indicate that disruption of this signaling might serve as a novel therapeutic target for metastatic disease.Khalil BD, Hsueh C, Cao Y, Abi Saab WF, Wang Y, Condeelis JS, et al. GPCR signaling mediates metastasis via PI3Kβ. Cancer Research; Published OnlineFirst March 24, 2016; doi:10.1158/0008-5472.CAN-15-1675.Using genome-wide methylation profiling of 323 CNS-PNETs (primitive neuroectodermal tumors of the central nervous system) diagnosed by histology and 211 known brain tumor entities, Sturm and colleagues showed that CNS-PNET did not group together and that 61% of CNS-PNET's could be reclassified as other known brain tumors. For the remaining 39%, whole genome sequencing and RNA sequencing revealed recurrent complex interchromosomal translocations, which defined new entities termed CNS neuroblastoma with FOXR2 activation, CNS Ewing sarcoma family tumor with CIC alteration, CNS high-grade neuroepithelial tumor with MN1 alteration, and CNS high-grade neuroepithelial tumor with BCOR alteration. These activating lesions are potentially actionable using demethylating agents, bromodomain inhibitors, WNT inhibitors, and BCL6 inhibitors, opening up the possibility of rational targeted therapies for a rare childhood tumor with a historically poor prognosis.Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DTW, Capper D, et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 2016;164:1060–72.Casey and colleagues demonstrate that MYC directly regulates the transcription of both the innate and adaptive immune regulatory genes encoding CD47 and PD-L1 (CD274) from a range of mouse and human MYC-overexpressing cancer cells. MYC-overexpressing tumor cells that constitutively expressed CD47 or PD-L1 did not recruit CD4+ T-cells or other antitumor immune cells. These tumors also failed to regress when MYC was inhibited. The absence of antitumor immune cells resulted in sustained tumor angiogenesis and an abrogation of tumor cellular senescence previously observed in these models following MYC inactivation. These provocative findings suggest that (i) MYC shields tumors from antitumor immune cells, (ii) targeting MYC may elicit strong antitumor responses, and (iii) MYC-overexpressing tumors show particular susceptibility to immune checkpoint therapies.Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 2016 Mar 10. doi: 10.1126/science.aac9935. [Epub ahead of print].The utility of mouse xenograft models of human estrogen receptor positive (ER+) breast cancer is limited by the puzzling fact that high-level ER-supplementation is necessary to support their growth in mice. Sflomos and colleagues observed the requirement for the high ER-levels to relate to high stromal TGFβ levels encountered by cells injected into the mammary fat pad. TGFβ induces SLUG (SNAI2) and drives basal reprogramming of the luminal-type ER+ cancer cells. Interestingly, intraductal injections of the cancer cells overcame this problem. The more natural environment of the mammary duct maintained the luminal ER+ phenotype of the xenografted cells under physiological hormone levels and also gave rise to spontaneous metastases. Importantly, this mouse model was also suitable for patient-derived xenografts (PDX) of ER+ tumors, a major advancement over the currently predominantly ER− PDX tumors. Given the importance of PDX tumors in translational cancer research, the intraductal model will enable research into physiologically relevant hormone responses in human breast cancer.Sflomos G, Dormoy V, Metsalu T, Jeitziner R, Battista L, Scabia V, et al. A preclinical model for ERα-positive breast cancer points to the epithelial microenvironment as determinant of luminal phenotype and hormone response. Cancer Cell 2016;29:407–22.The pH inside (pHi) cancer cells is higher than in normal cells and is linked to increased proliferation, migration, and apoptosis resistance. Although elevated expression of proteins that facilitate increased pHi (NHE1 for example) is reported in cancers, the role of increased pHi in progression in vivo remains unclear. Grillo-Hill and colleagues demonstrate that increased expression of NHE1 (SLC9A1) was sufficient to drive hyperplasia in the absence of other transforming cues. Furthermore, NHE1 synergized with oncogenic RASV12 to promote cancer development and migration in vivo. Conversely, deletion or pharmaceutical inhibition of NHE1 induced acidosis and synthetic lethality in RAS- and RAF-transformed, but not in normal cells. Thus, oncogenes can promote increased pHi in vivo and targeting pH levels could be exploited therapeutically and selectively to eradicate cancer cells.Grillo-Hill BK, Choi C, Jimenez-Vidal M, Barber DL. Increased H+ efflux is sufficient to induce dysplasia and necessary for viability with oncogene expression. Elife 2015;4:e03270.Although recently published data establishes the ALK inhibitor crizotinib as standard first-line therapy for therapy-naïve patients with ALK-fusion positive non-small-cell lung cancer, concerns remain about efficacy for targeted therapies in brain metastases, present in up to 30% of these patients. Intracranial efficacy was assessed prospectively in this study in patients with brain lesions treated with either crizotinib or with chemotherapy. Crizotinib was associated with better control of intracranial disease compared with conventional genotoxic agents (56% with crizotinib versus 25% with chemotherapy; P&lt;0.006), as well as improved progression free survival, objective response rate, and quality of life. The central nervous system (CNS) was previously thought to be a site of failure for crizotinib. With next-generation ALK inhibitors in the clinic, there is more optimism about treatment options for patients with CNS disease.Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, et al. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol 2016 Mar 28. doi: 10.1200/JCO.2015.63.5888. [Epub ahead of print].Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.